Cancer arises when a population of cells gains the ability to inappropriately grow and survive. These biological behaviors often result from genetic and environmental abnormalities that work together to trigger specific signaling pathways that promote the inappropriate growth and survival of malignant cells. In particular, protein tyrosine phosphorylation is understood to initiate powerful signals that govern many different aspects of cell behavior. A popular paradigm suggests that a balance between tyrosine kinase and phosphatase activities serves to dictate the cellular levels of protein tyrosine phosphorylation and thereby governs cellular decisions regarding growth, survival and invasiveness. This paradigm generally predicts that tyrosine kinases would be oncogenic whereas tyrosine phosphatases negatively regulate malignant transformation. Although this portioning is generally correct, emerging evidence reveals a more complex interplay between tyrosine kinases and phosphatases. For example, the PTPCAAX tyrosine phosphatase has been recently shown to function as a powerful oncogene. Moreover, the enzymatic activity of Src family kinases is liberated by phosphatase-mediated dephosphorylation of important tyrosine residues. In the latter situation, phosphatases can actually up-regulate protein tyrosine phosphorylation by increasing the enzymatic activity of kinases:
The EphA2 receptor tyrosine kinase is overexpressed in a large number of human cancers. High levels of EphA2 apply to a large number of different cancers, including breast, prostate, colon and lung carcinomas as well as metastatic melanomas. Moreover, the highest levels of EphA2 are consistently found on the most aggressive cell models of human cancer. EphA2 is not simply a marker of malignant disease as ectopic overexpression of EphA2 is sufficient to confer tumorigenic and metastatic upon non-transformed epithelial cells.
Cancer cells also display differences in EphA2 function as compared with non-transformed epithelia. Despite being present at relatively low levels in non-transformed epithelial cells, EphA2 in these cells is prominently tyrosine phosphorylated. In contrast, the EphA2 in malignant cells is not tyrosine phosphorylated even though it is grossly overexpressed in these cells. These differences in EphA2 phosphotyrosine content are important because tyrosine phosphorylated EphA2 negatively regulates tumor cell growth and invasiveness whereas unphosphorylated EphA2 promotes these same behaviors in malignant cells. The association of EphA2 with malignancy is further detailed in international patent applications WO 01/12172 and WO 01/12804.